CONVULSANT EFFECTS OF SOME XANTHINE - DERIVATIVES IN GENETICALLY EPILEPSY-PRONE RATS

The behavioural and electrocorticographic (ECoG) convulsant effects: o f several xanthine derivatives injected intraperitoneally (i.p.) were studied in genetically-epilepsy prone rats. The aim of the study was t o evaluate the relationship among convulsant potency, molecular struct ure and lipophilicity of some xanthines. Animals were injected i.p. wi th various doses (250-1000 mu mol/kg) and a different convulsant poten cy was observed among the various xanthines tested. IBMX (3-isobutyl-1 -methylxanthine), theophylline (1,3-dimethylxanthine) and caffeine (1, 3,7-trimethylanthine) induced an epileptogenic pattern that consisted in an initial phase characterized by wet-dog shakes followed by head t remor, nodding, clonic convulsion and they appeared to be the most pot ent xanthines among those studied. During seizures, the electrocortica l activity was usually characterized by single or multiple sharp- or s pike-wave episodes followed by polyspike discharges. After the highest doses of IBMX, theophylline and caffeine, the animals react with fall ing down, transient tonic clonic seizures, escape response and general ized seizures followed by post-ictal period. Equimolar doses of 8-chlo rotheophylline and theobromine (3,7-dimethylxanthine) produced less ev ident epileptic responses in comparison to previous compounds, whereas no epileptic signs were observed following the administration of enpr ofylline (3-propylxanthine), etofylline [7-(2-hydroxyethyl)theophyllin e], diprophylline [7-(2,3-dihydroxy-propyl)theophylline] and doxofylli ne [7-(1,3-dioxolan-2-ylmethyl) theophylline]. Lipophylicity of the co mpounds was determined, but no convincing correlations were found betw een the rank order of lipophilicities and the convulsant potencies of the compounds studied. On the other hand, structure-activity relations hip was also investigated. We suggest that the substitution pattern on the xanthine nucleus may explain. in part, the different convulsant p otency of the compounds studied. Furthermore, a selective antagonism o f adenosine subtype receptors should be considered.